Our understanding of mechanisms that contribute to the pathogenesis of motor neuron disease (MND) remains incomplete. While much effort has been focused on understanding why motor neurons die in MND, little attention has been paid to the possible role of the motor terminal in the pathogenesis of motor unit dysfunction. In a canine version of MND (Hereditary Canine Spinal Muscular Atrophy, HCSMA), we have demonstrated that loss of motor unit function occurs at the neuromuscular junction (NMJ) by mechanisms that compromise synaptic transmission but do not involve detectable degeneration of the motor terminal or axon, Thus, in HCSMA., loss of motor unit function precedes even degeneration in the periphery. We do not know whether these phenomena are specific for HCSMA. Thus, one goal of the present work will be to extend the type of analysis we have performed in HCSMA to another model of MND, the SOD1 transgenic mouse. Our first Aim will be to confirm preliminary data that extensive denervation of muscle precedes the onset of motor neuron cell death in the spinal cord of SOD1 transgenic mice. In another aim, we will collect evidence to support the idea that a version of excitotoxicity underlies NMJ degeneration that is related to decreased calcium handling capacity. Preliminary data we have obtained indicate that NMJ degeneration in SOD1 mice is not simply a matter of presynaptic loss but may reflect an interactive process with muscle that may require muscle fiber activity and resembles in many ways the process of NMJ synapse elimination observed during normal postnatal development. We will test several hypotheses suggested by these observations. In another study, we will determine whether antagonists for calcium-activated proteases known to exist and operate in motor terminals (calpains) can inhibit NMJ degeneration in SOD1 mice. The results of this work will determine whether loss of motor unit function in the SOD1 transgenic mouse model of MND occurs as a result of motor terminal dysfunction. [unreadable] [unreadable]